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Hypoxia-Inducible Factor 1-Alpha Reduces Infarction and Attenuates Progression of Cardiac Dysfunction After Myocardial Infarction in the Mouse

Masakuni Kido, MD^_*, Lingling Du, MD^_*, Christopher C. Sullivan, MS^_*, Xiaodong Li, MD, PhD^_*, Reena Deutsch, PhD, Stuart W. Jamieson, MB, FRCS^_* and Patricia A. Thistlethwaite, MD, PhD^_*,_*

^_* Division of Cardiothoracic Surgery
Division of Biostatistics, University of California, San Diego, San Diego, California

View larger version (23K): [in a new window]   Figure 1 Echocardiographic measurement of akinetic area correlates with pathologic measurement of infarct size at 24 h (top panel) and 4 weeks (bottom panel) after coronary ligation. Linear regression analysis of the correlation between the percent infarction area/total ventricular area (as measured by TTC or Masson trichrome staining/histology at 24 h and 4 weeks after coronary ligation, respectively) and the percent akinetic area/total ventricular area as measured by two-dimensional echocardiography. For both timepoints n = 20 animals; 10 HIF-1(+) (circles), 10 HIF-1(–) (triangles).

View larger version (52K): [in a new window]   Figure 2 Northern blot analysis of transgenic and endogenous HIF-1 in infarct, peri-infarct, and remote left ventricular regions at 24 h and 4 weeks after LAD ligation and in sham-operated hearts. + = HIF-1(+) hearts; – = HIF-1(–) hearts. Steady-state levels of transgenic HIF-1 mRNA are not affected by hypoxic conditions, while steady-state levels of endogenous HIF-1 mRNA are increased in early infarct and peri-infarct regions.

View larger version (61K): [in a new window]   Figure 3 HIF-1(+) transgenic hearts show increased expression of HIF-1, VEGF, and iNOS in the peri-infarct region compared to control HIF-1(–) hearts. (A) Western blot analysis of HIF-1, VEGF, and iNOS in infarct, peri-infarct, and remote left ventricular regions at 24 h and 4 weeks after LAD ligation and in sham-operated hearts. + = HIF-1(+) hearts; –= HIF-1(–) hearts. (B) Immunohistochemical localization of HIF-1, VEGF, and iNOS protein in peri-infarct areas at 4 weeks in HIF-1(+) and HIF-1 (–) hearts. Sections were counterstained with hematoxylin. Scale bar = 80 µm.

View larger version (42K): [in a new window]   Figure 4 Capillary densities at different locations in the infarcted heart. CD31-positive capillary density was measured at three areas: (A) infarction, (B) peri-infarct border zone, and (C) interventricular septum and similar anatomic areas in sham-operated hearts. The number of CD31-stained capillaries was counted in a blinded fashion and expressed as the number/mm2. HIF-1(+)/MI n = 10 animals, HIF-1(–)/MI n = 10 animals, HIF-1(+)/sham n = 10 animals, HIF-1(–)/sham n = 10 animals.

View larger version (86K): [in a new window]   Figure 5 Histology of infarcted hearts. Four weeks after infarction, hearts were excised, sectioned at the level of the papillary muscles, and stained with Masson's trichrome (A, scale bar = 1 mm, B, scale bar = 200 µm). More preservation of muscular architecture and greater number of peri-infarct vessels seen in HIF-1(+) hearts compared to HIF-1(–) controls. Immunohistochemical staining with anti-CD31 monoclonal antibody in HIF-1(+) and HIF-1(–) hearts (n = 10 for each group) 4 weeks after coronary ligation in the peri-infarct region (C, scale bar = 45 µm).